title: A new p53 target gene, RKIP, is essential for DNA damage-induced cellular senescence and suppression of ERK activation.
abstract: p53, a strong tumor suppressor protein, is known to be involved in cellular senescence, particularly premature cellular senescence. Oncogenic stresses, such as Ras activation, can initiate p53-mediated senescence, whereas activation of the Ras-mitogen-activated protein kinase (MAPK) pathway can promote cell proliferation. These conflicting facts imply that there is a regulatory mechanism for balancing p53 and Ras-MAPK signaling. To address this, we evaluated the effects of p53 on the extracellular signal-regulated kinase (ERK) activation and found that p53 could suppress ERK activation through de novo synthesis. Through several molecular biologic analyses, we found that RKIP, an inhibitor of Raf kinase, is responsible for p53-mediated ERK suppression and senescence. Overexpression of RKIP can induce cellular senescence in several types of cell lines, including p53-deficient cells, whereas the elimination of RKIP by siRNA or forced expression of ERK blocks p53-mediated cellular senescence. These results suggested that RKIP is an essential protein for cellular senescence. Moreover, modification of the p53 serine 46 residue was critical for RKIP induction and ERK suppression as well as cellular senescence. These results indicated that RKIP is a novel p53 target gene that is responsible for p53-mediated cellular senescence and tumor suppressor protein expression.
authors.affiliation: Department of Molecular Biology, College of Natural Science, Pusan National University, Pusan, Republic of Korea.
authors.forename: Su-Jin
authors.initials: SJ
authors.lastname: Lee
authors.forename: Sun-Hye
authors.initials: SH
authors.lastname: Lee
authors.forename: Min-Ho
authors.initials: MH
authors.lastname: Yoon
authors.forename: Bum-Joon
authors.initials: BJ
authors.lastname: Park
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000235:genetics*; D004249:DNA Damage; D004317:Doxorubicin / Q000494:pharmacology; D004789:Enzyme Activation; D005047:Etoposide / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D049488:Phosphatidylethanolamine Binding Protein / Q000235:genetics* / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C511482:PEBP1 protein, human; D049488:Phosphatidylethanolamine Binding Protein; D059005:Topoisomerase II Inhibitors; D016159:Tumor Suppressor Protein p53; D005047:Etoposide; D004317:Doxorubicin; D048049:Extracellular Signal-Regulated MAP Kinases